Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs

Richard L. Mackman, Lijun Zhang, Vidya Prasad, Constantine G. Boojamra, Janet Douglas, Deborah Grant, Hon Hui, Choung U. Kim, Genevieve Laflamme, Jay Parrish, Antitsa D. Stoycheva, Swami Swaminathan, Ke Yu Wang, Tomas Cihlar

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Abstract

Phosphonomethoxy nucleoside analogs of the thymine containing nucleoside reverse transcriptase inhibitors (NRTIs), 3′-azido-2′,3′-dideoxythymidine (AZT), 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), and 2′,3′-dideoxythymidine (ddT), were synthesized. The anti-HIV activity against wild-type and several major nucleoside-resistant strains of HIV-1 was evaluated together with the inhibition of wild-type HIV reverse transcriptase (RT). Phosphonomethoxy analog of d4T, 8 (d4TP), demonstrated antiviral activity with an EC50 value of 26 μM, whereas, phosphonomethoxy analogs of ddT, 7 (ddTP), and AZT, 6 (AZTP), were both inactive at concentrations up to 200 μM. Bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs improved the anti-HIV activity of 7 and 8 by >150-fold and 29-fold, respectively, allowing for antiviral resistance to be determined. The K65R RT mutant virus was more resistant to the bisPOC prodrugs of 7 and 8 than bisPOC PMPA (tenofovir DF) 1. However, bisPOC prodrug of 7 demonstrated superior resistance toward the RT virus containing multiple thymidine analog mutations (6TAMs) indicating that new phosphonate nucleoside analogs may be suitable for targeting clinically relevant nucleoside resistant HIV-1 strains.

Original languageEnglish (US)
Pages (from-to)5519-5528
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number16
DOIs
StatePublished - Aug 15 2007

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Keywords

  • Antiviral
  • Nucleosides
  • Phosphonates
  • Resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Mackman, R. L., Zhang, L., Prasad, V., Boojamra, C. G., Douglas, J., Grant, D., Hui, H., Kim, C. U., Laflamme, G., Parrish, J., Stoycheva, A. D., Swaminathan, S., Wang, K. Y., & Cihlar, T. (2007). Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs. Bioorganic and Medicinal Chemistry, 15(16), 5519-5528. https://doi.org/10.1016/j.bmc.2007.05.047